1. Field of the Invention
The present invention relates to bis(5-aryl-2-pyridyl) derivatives or salts thereof, and also to medicinal compositions which comprise the bis(5-aryl-2-pyridyl) derivatives or salts thereof as active ingredients and are useful for the prevention or treatment of allergic immune diseases.
2. Discussion of the Background
IgE, a class of immunoglobulin (Ig), is an allergen-specific molecule produced by IgE producing cells differentiated from B cells, when triggered by contact of immunocytes with an allergen in the body.
IgE is produced in an organ targeted by allergy, and binds to a receptor on surfaces of mast cells which are the principal effector cells in an allergic reaction or basophils (sensitized state). From the mast cells, which are stimulated as a result of intrusion of the allergen into the body after sensitization and the accompanying reaction with the specific IgE, allergic chemical mediators such as histamine, leucotrienes, prostaglandins and PAF, and tissue destructive enzymes such as tryptase are released thereby provoking the immediate responses of an allergic reaction such as increased vasopermeability, smooth muscle constriction or vasodilation. From the stimulated mast cells, cytokines, such as IL-4, which directly activate other immune system cells are also secreted. As a result, eosinophils, basophils or the like infiltrate tissues, and allergic chemical mediators or tissue destructive proteins such as MBP, which are secreted by these inflammatory cells, induces late responses of an allergic reaction to protract and worsen an allergic symptom.
As can be appreciated from the foregoing remarks, an abnormality in IgE production is highly relevant to various allergic immune diseases such as asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel disease, contact dermatitis and allergic ophthalmopathy. It is known that inhibition of IgE production makes it possible to prevent and/or treat these diseases (Emerging Therapeutic Targets In Asthma And Allergy: Modulation Of IgE, Emerging Therapeutic Targets, 3, 229-240 (1990); Anti-IgE As Novel Therapy For The Treatment Of Asthma, Curr. Opin. Plum. Med., 5, 76-80 (1999); Treatment Of Allergic Asthma With Monoclonal Anti-IgE Antibody, N. Eng. J. Med., 341, 1966-1973 (1999); Anti-IgE Antibody Therapy For Asthma, N. Eng. J. Med., 341, 2006-2008 (1999)).
From the foregoing, IgE is believed to be a substance which takes part in the manifestation of an allergic disease at the onset of the disease. With the objective of developing antiallergic agents, some small molecules with IgE antibody production inhibiting activity have been found and reported to date (WO 98/04058, WO 98/07702, WO 98/16497, JP 10-324631A, WO 99/19291, WO 99/35140, WO 99/38829, WO 99/42446, JP 11-269192A, WO 00/05198, xe2x80x9cYakuri to Chiryo (Basic Pharmacology and Therapeutic)xe2x80x9d 22(3), 1369 (1994), JP 1-106818A, JP 7-17506B, JP 8-92216A, JP 8-109177A, WO 96/11682, JP 59-167564A). These compounds, however, involve problems such as low solubility in water, and therefore they are not entirely satisfactory agents in the therapeutic treatment of allergic disease.
Accordingly, one object of the present invention is to provide a compound having excellent IgE antibody production inhibiting activity and also a medicinal composition comprising the compound as an active ingredient.
Briefly, this object and other objects of the present invention as hereinafter will become more readily apparent can be attained by a bis(5-aryl-2-pyridyl) compound having the following formula (1) or a salt thereof: 
wherein A is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group, and X is a substituent selected from the group consisting of formulas (2) to (5): 
wherein, in formula (2), m is an integer of 1 or 2; in formula (3), n is an integer of 1 to 6; and in formula (4), R is hydrogen or lower alkyl and p is an integer of 1 to 6.
Another aspect of the present invention is a medicinal composition comprising the active bis(5-aryl-2-pyridyl) compound or the salt thereof of the invention.
Still another aspect of the present invention is a medicinal composition comprising the active bis(5-aryl-2-pyridyl) compound or the salt thereof in combination with a pharmacologically acceptable carrier.
Yet another aspect of the present invention is a method of treating a subject for an allergic immune disease by administering the bis(5-aryl-2-pyridyl) derivative or the salt thereof of the invention to a subject.
As a result of the investigative work by the present inventors, the present compound has been found to exhibit an excellent IgE antibody production inhibiting activity and also good solubility in water, and therefore are useful in the treatment of allergic immune diseases.
Illustrative of the lower alkyl moiety in xe2x80x9clower alkyl groupsxe2x80x9d, xe2x80x9chalogeno(lower alkyl) groupsxe2x80x9d, xe2x80x9chydroxy(lower alkyl) groupsxe2x80x9d, xe2x80x9clower alkoxy(lower alkyl) groupsxe2x80x9d, xe2x80x9clower alkoxy groupsxe2x80x9d, xe2x80x9c(lower alkyl)thio groupsxe2x80x9d, xe2x80x9c(lower alkyl)amino groupsxe2x80x9d, xe2x80x9c(lower alkyl)sufonylamino groupsxe2x80x9d, xe2x80x9c(lower alkoxy)carbonyl groupsxe2x80x9d and xe2x80x9clower alkanoyl groupsxe2x80x9d as used herein are linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms. Suitable examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, and cyclohexyl. Further, suitable halogen atoms include fluorine, chlorine, bromine and iodine.
In formula (1), the aromatic hydrocarbon group represented by A preferably has 6 to 14 carbon atoms, with phenyl or naphthyl being more preferred and phenyl being particularly preferred. Preferred examples of the aromatic heterocyclic group include 5- to 10-membered heterocyclic groups each of which contains one or two nitrogen, oxygen or sulfur atoms, with pyridyl, thienyl, furyl, benzofuryl and benzothienyl groups being more preferred. These groups may contain 1 to 3 substituents. Suitable examples of such substituents include lower alkyl groups, halogeno(lower alkyl) groups, hydroxy(lower alkyl) groups, lower alkoxy(lower alkyl) groups, lower alkoxy groups, halogen atoms, hydroxy group, cyano group, (lower alkyl)thio groups, amino group, mono- or di-(lower alkyl)amino groups, (lower alkyl)sufonylamino groups, formyl group, carboxyl group, (lower alkoxy)carbonyl groups, lower alkanoyl groups, pyrrolidinyl group and alkylenedioxy groups.
Preferred specific examples of these substituents include methyl, t-butyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methoxy, ethoxy, isopropoxy, fluoro, chloro, hydroxy, cyano, methylthio, amino, dimethylamino, methanesulfonylamino, pyrrolidinyl, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, acetyl, and methylenedioxy.
Among the groups represented by X, preferred is the group of formula (3) in which n is an integer of 2 to 4 and the group of formula (4) in which p is an integer of 2 to 4.
Preferred specific examples of the bis(5-aryl-2-pyridyl) derivative (1) of the present invention include 1,4-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine dimethanesulfonate, 1,4-bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine tetrahydrochloride, 1,4-bis[5-(4-dimethylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine, 1,3-bis[4-[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-1-piperazinyl]propane, and N,Nxe2x80x2-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-N,Nxe2x80x2-dimethylethylenediamine dimethanesulfonate.
Compound (1) of the present invention can be produced, for example, by the following sequence of reaction steps, although no particular limitation is imposed on the method of synthesis employed. 
wherein A and X have the same meanings as defined above, Y1 and Y2 each are halogen orxe2x80x94OSO2(CqF2q+1) in which q is 0 or an integer of 1 to 4, and Z is dihydroxyboron, di(lower alkoxy)boron, di(lower alkyl)boron, dihalo(lower alkyl)silicon, halogenated zinc, tri(lower alkyl)tin, halogenated magnesium or the like.
Specifically, compound (1) of the present invention can be produced by reacting compound (6) with compound (7) in the absence of a solvent or in a solvent optionally in the presence of a base to prepare compound (8) and then reacting compound (8) with compound (9).
Suitable examples of the solvent employed in the reaction (condensation reaction) between compound (6) and compound (7) include toluene, tetrahydrofuran, dioxane and dimethylformamide, whereas examples of the base employable in the reaction include potassium carbonate and sodium hydride. The reaction is preferably conducted at room temperature to 200xc2x0 C. for 0.5 to 100 hours, notably at 80 to 120xc2x0 C. for 2 to 15 hours.
To prepare compound (1) of the present invention, the reaction (cross-coupling reaction) between compound (8) and compound (9) can be conducted by adding compound (9) and a catalyst to a solution or suspension of compound (8) and allowing compound (8) to react with compound (9) optionally in the presence of a ligand and a base (Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VHC: Weinheim (1998). Stanforth, S. P., Tetrahedron, 54, 263-303 (1998)).
Suitable examples of a solvent employable in the above reaction include benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, acetonitrile, dimethylformamide, N-methylpiperidone, methanol, ethanol, and water. Suitable examples of the catalyst include tetrakis(triphenylphosphine)palladium(0), tris(bisbenzylideneacetone)dipalladium(0), palladium(II) acetate, palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), dichloro[1,2-bis(diphenylphosphino)ethane]palladium(II), dichloro[1,4-bis(diphenylphosphino)butane]palladium(II), dichloro[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]palladium(II), tetrakis(triphenylphosphine)nickel(0) and bis(acetylacetonato)nickel(II).
Suitable examples of the ligand, on the other hand, include tri(t-butyl)phosphine, triphenylphosphine, tri(o-tolyl)phosphine, tri(2-furyl)phosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene. Suitable examples of the base include sodium acetate, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, cesium fluoride, tributylammonium fluoride, and triethylamine.
As to the reaction conditions, the reaction may be conducted at room temperature up to a temperature of 150xc2x0 C. for 0.5 to 100 hours. It is, however, preferred to follow the details of the reaction reported by Suzuki et al, (Miyaura, N.; Suzuki, A., Chem. Rev., 95, 2457-2483 (1995)). Here, compound (9) is employed in which Z is dihydroxyboron and the reaction is conducted under conditions of tetrakis(triphenylphosphine)palladium(0)/potassium carbonate (or sodium carbonate)/water-methanol(or ethanol)-toluene/60 to 100xc2x0 C./0.5 to 3 hours; or a compound (9) in which Z is di(lower alkoxy)boron is reacted under conditions of dichloro[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]palladium (II)/1,1xe2x80x2-bis(diphenylpbosphino)ferrocene/sodium carbonate/water-dimethylformamide/60 to 100xc2x0 C./0.5 to 3 hours.
The compounds obtained in the above reactions, respectively, can be isolated and purified by subjecting them to purification procedures commonly employed in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, one or more of various types of chromatography, and the like. Further, the intermediate can be provided for use in the next reaction without the need of specifically purifying the compound.
In addition, the product and intermediate may also be obtained in the form of solvates with reaction solvents, recrystallization solvents or the like, especially as hydrates. Further, compound (1) of the present invention may include various isomers depending on the kinds and combination of substituents in the molecule. It is to be noted that the present invention encompasses all of such isomers.
Compound (1), obtained as described above, can be converted into an acid addition salt or a basic salt by a method known per se in the art. No particular limitation is imposed on such salts insofar as they are pharmacologically acceptable salts. When compound (1) is a basic compound, examples of a pharmacologically acceptable salt thereof include mineral acid salts such as the hydrochloride, sulfate and nitrate; and organic acid salts such as the methanesulfonate, acetate, oxalate and citrate. When compound (1) is an acidic compound, on the other hand, examples of pharmacologically acceptable salts thereof include alkali metal salts such as the sodium and potassium salts; alkaline earth metal salts such as the calcium and magnesium salts; and organic base salts such as the pyridine, picoline and triethylamine salts.
The bis(5-aryl-2-pyridyl) compound (1) of the present invention has excellent IgE antibody production inhibiting activity as is demonstrated in tests described below, as well as IL-4 production inhibiting activity and IL-5 production inhibiting activity. The compound is useful as medicinal agent for the prevention or treatment of various allergic diseases, for example, asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel disease, contact dermatitis and allergic ophthalmopathy, and also as an IgE antibody production inhibitor.
The medicinal composition of the present invention comprises, as an active ingredient, the bis(5-aryl-2-pyridyl) compound or a salt thereof. By adding pharmacologically acceptable, inorganic or organic carriers, the bis(5-aryl-2-pyridyl) compound or salt thereof can be formulated into medicinal compositions, for example, various oral preparations or parenteral preparations such as solid, semi-solid or liquid preparations by methods known per se in the art.
Illustrative of preparations for oral administration are tablets, pills, granules, soft or hard capsules, triturates, subtilized granules, powders, emulsions, syrups, pellets, and elixirs. On the other hand, illustrative preparations for parenteral administration include injectable formulations, drips, infusions, ointments, lotions, tonics, sprays, suspensions, medicinal oils, emulsions, suppositories, and instillations.
To formulate such preparations, methods known per se in the art can be followed. The active ingredient of the present invention can be used in combination with pharmacologically acceptable surfactants, excipients, coloring agents, flavoring agents, preservatives, stabilizers, buffering agents, suspending agents, isotonicities and the like as needed.
The dosage of the therapeutic agent of the present invention varies inter alia depending on the compound, the disease to be treated or prevented, the method of administration, the period of treatment, and the age, sex and weight of the patient. Nonetheless, it is preferred to administer the medicine at a daily dosage ranging from 0.01 to 1,000 mg/kgxc2x7weight in terms of the compound represented by formula (1). This dosage can be administered at once or in several portions, for example, 2 to 6 portions in a day.
Having now generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.